A Single-arm, Open-label, Phase II Study of CHeckpoint Inhibitors in Men With prOgressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

2019-10-01 07:55:01 | BioPortfolio


The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in Veterans with metastatic castration-resistant prostate cancer (mCRPC) characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to PSA progression, maximal PSA response, time to initiation of alternative anti-neoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pre-treatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.


Research Plan:

This is a single-arm, open-label phase II study that examines the response rate of pembrolizumab in metastatic castration-resistant prostate cancer (mCRPC) patients who have either a mismatch repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-). The study will enroll mCRPC patients who have the selected genetic mutation and at least one metastatic lesion that is amendable to biopsy. All patients must have progressed on at least one prior line of mCRPC therapy, such as abiraterone acetate or enzalutamide. Eligible patients will undergo at least 12 weeks (4 cycles) of pembrolizumab (200 mg IV).


Patients with either a mismatch repair deficiency or biallelic inactivation of CDK12 in their tumor are eligible for this study. If the patient has progressed on at least one prior therapy for mCRPC, including abiraterone acetate or enzalutamide, he is eligible to begin genetic screening. Patients with these mutations will be identified primarily through standard of care genetic testing with either archival tissue or blood. Specimens will be sent to VA approved vendors for genetic testing to determine if the patient has the necessary mutations to receive the study drug (pembrolizumab). If eligible, the patient will sign the Main Treatment ICF and proceed with the screening procedures. Once enrolled the patient will undergo a biopsy of a metastatic lesion (baseline biopsy) to identify molecular correlates. If the patient does not have any archival tissue or blood to be used to identify genetic mutations, the biopsy of a metastatic lesion will be used to both identify genetic mutations and to identify molecular correlates.

When the patient has met all the eligibility criteria, he will receive pembrolizumab. Pembrolizumab will be administered at a starting dose of 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. During the treatment, patients will either simultaneously receive a GnRH analogue or undergo a bilateral orchiectomy prior to treatment to maintain a castrate level of testosterone ( 50 ng/dl). At progression, patients will undergo a second biopsy of the same metastatic lesion of the baseline biopsy. The baseline (pre-treatment) and at-progression biopsies will be used for correlative analyses to determine the efficacy of pembrolizumab.

Note: after the testing process is complete, Oncoplex will return any remaining sample back to the Department of Pathology at the West LA VA Medical Center. These specimens will be stored in Dr. Matthew Rettig's biorepository on site for analysis and future research.


Since this is a new study, the results have not yet been obtained. The primary endpoint of this study is to measure the objective response rate, radiographic progression free survival at 6 months, and decline in PSA of 50% or more 12 weeks of therapy.

Clinical Significance:

There are 230,000 new incidences of prostate cancer and 30,000 deaths from prostate cancer per year in the US. It is the second most common cause of death in American men. Importantly, prostate cancer is diagnosed in more than 12,000 US Veterans each year, representing nearly one third of all cancer diagnoses in Veterans.

Metastatic prostate cancer is incurable, and its treatment is palliative. However, many Veterans with metastatic castration-resistant prostate cancer (mCRPC) progress despite experiencing some clinical benefit from hormonal therapy and chemotherapy. As a result, novel therapies that provide a robust clinical benefit and have a good safety profile are needed for these patients.

Immunotherapies, such as checkpoint inhibitor, for mCRPC patients that have either a mismatch repair deficiency (dMMR) or a biallelic inactivation of CDK12 (CDK12-/-) is an attractive therapy, especially since therapies involving checkpoint inhibitors have exhibited significant improvements in patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and many other cancers. The results of this study will establish the ideal subset of mCRPC patients who will benefit from the study drug. Importantly, the correlative studies will provide critical insight into the mechanisms of primary and acquired resistance that occur despite selection of patients with CDK12-/- or dMMR. This result can inform further selection of patients for checkpoint inhibition, as well as identify other potential therapies that can be co-administered with pembrolizumab to prevent or overcome resistance to checkpoint inhibitors.

Study Design


Metastatic Castration Resistant Prostate Cancer




VA Greater Los Angeles Healthcare System, West Los Angeles, CA
West Los Angeles
United States


Not yet recruiting


VA Office of Research and Development

Results (where available)

View Results


Published on BioPortfolio: 2019-10-01T07:55:01-0400

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Medical and Biotech [MESH] Definitions

An androstene derivative that inhibits STEROID 17-ALPHA-HYDROXYLASE and is used as an ANTINEOPLASTIC AGENT in the treatment of metastatic castration-resistant PROSTATE CANCER.

Tumors or cancer of the PROSTATE which can grow in the presence of low or residual amount of androgen hormones such as TESTOSTERONE.

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A glycoprotein that is a kallikrein-like serine proteinase and an esterase, produced by epithelial cells of both normal and malignant prostate tissue. It is an important marker for the diagnosis of prostate cancer.

A synthetic retinoid that is used orally as a chemopreventive against prostate cancer and in women at risk of developing contralateral breast cancer. It is also effective as an antineoplastic agent.

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